The importance of the LDL receptor family proteins in lipid metabolism and protection against cardiovascular and Alzheimer's diseases is well established in the literature. However, the importance of these receptor functions in modulating sensitivity to diet-induced obesity and obesity-related diabetes has not been explored. This project will focus on the influence of two members of the LDL receptor family proteins, namely VLDL receptor (VLDLR) and LDL receptor-related protein LRP-1, in diet-induced obesity and diabetes. Preliminary results showed that VLDLR'/~ mice were resistant to obesity and diabetes after feeding a high fat-high sucrose diabetogenic diet. In contrast, the receptor associated protein (RAP)-deficient LRPAP'~ mice, which displayed compromised overall LRP-1 functions but maintained VLDLR functions in adipose and skeletal muscle, were insulin resistant even when maintained on a basal low fat/low sucrose diet. Interestingly, mice with increased circulating levels of apoE-containing lipoproteins (liver-specific apoE3 transgenic mice) were similar to wild type mice in body weight gain in response to the diabetogenic diet, but remained insulin sensitive without hyperglycemia. Based on these observations, the overall hypothesis of this project is that the level of expression of these LDL receptor family proteins in various high energy metabolism tissues modulates lipid and glucose partitioning in these tissues and adipokine production in adipocytes, and thus is an important determinant of diet-induced obesity and diabetes. Aim 1 will delineate the mechanism responsible for the difference between wild type, VLDLR''', and apoE-transgenic (apoE-tg) mice in diet-induced obesity and diabetes, testing the hypothesis that the VLDLR-mediated lipid uptake pathway is a key modulator of fat versus glucose utilization by heart, muscle, and adipose tissues, and thus is contributory to diet-induced obesity and diabetes. This aim will also test the hypothesis that the anti- inflammatory and anti-oxidative properties of apoE protect against obesity-related diabetes independent of lipid transport. Aim 2 will generate tissue specific VLDLR transgenic mice in VLDLR*'* and VLDLR"7 background to evaluate the importance of VLDLR expression in muscle, heart, versus adipose tissue in modulating diet-induced obesity and diabetes. Aim 3 will produce liver-, muscle-, and adipose-specific knockouts of LRP-1 to evaluate its specific role in each tissue in relationship to diet-induced obesity and insulin resistance, testing the hypothesis that LRP-1 expression in adipose is essential for lipid deposition and storage in this tissue and protects against diabetes whereas LRP-1 in muscle promotes diabetes by facilitating lipid uptake by this tissue. Results from these studies will offer strategies toward designing novel therapeutics that optimize fat and glucose distribution and limit insulin resistance and obesity.